Methods and compositions relating to a cardiac-specific nuclear regulatory factor

Abstract

The present invention relates to a novel cardiac-specific transcription factor, myocardin. This molecule modulates the development and differentiation of cardiomyocytes and is a potent inhibitor of cell growth. Methods to exploit these observations are provided and include respecifiying non-cardiac cells into cardiac cells, stimulating cardiac tissue regeneration, and methods for treating cardiomyopathies, myocardial infarction.

Description

[0001]This application claims benefit of priority to U.S. Provisional Application Ser. No. 60 / 257,761 filed Dec. 21, 2000.[0002]The government owns rights in the application pursuant to NIH Grant Nos. P01 HL49953 and HL63926.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The present invention relates generally to the fields of developmental biology and molecular biology. More particularly, it concerns proteins involved in the regulation of cardiomyocyte cell growth and development.[0005]2. Description of Related Art[0006]The leading cause of morbidity and mortality in industrialized countries is heart disease, particularly heart disease that is associated with myocardial infarction. Myocardial infarction results in the loss of cardiomyocytes. Cardiomyocytes are post-mitotic cells and generally do not regenerate after birth. Furthermore, it has been discovered that they respond to mitotic signals by cell hypertrophy (Kodama et al., 1997; Pan et al., 1997) rather than...

AI Technical Summary

Benefits of technology

[0016]As discussed above, heart disease, especially that resulting in a heart attack, typically results in significant cardiac dysfunction. This dysfunction can be the result of the activities of cells, especially non-cardiomyocyte cells, in the region of disease of the heart. In a further aspect of the present invention, compositions and methods are provided that alleviate the deleterious activities of such non-cardiomyocyte target cells on the functioning of the heart by modulating the phenotype of said target cells. In preferred embodiments, the compositions and methods not only alleviate the deleterious activities of the target cell population but stimulate the target cells to engage in one or more functions typical of cardiomyocytes thereby improving myocardial functioning in the diseased region. By way of illustration, fibroblast cells typically are recruited to form scar tissue in areas of myocardium where cardiomyocyte necrosis has occurred (for example, as the result of myocardial infarction) thereby resulting in permanent, regional cardiac dysfunction. Introduction of a composition in accordance herewith into such fibroblasts can prevent those cells from engaging in such deleterious activity and, in preferred embodiments, can actually stimulate the fibroblasts to engage in one or more functions phenotypical of cardiomyocytes (for example, spontaneous beating, formation of microtubules or adjoining to neighboring cells via intercalated discs, and expression of cardiomyocyte specific genes, such as homeobox gene Nkx2.5, alpha-myosin heavy chain and atrial natriuretic factor) thereby assisting heart function. Advantageously, introduction of such compositions in accordance herewith may additionally improve the functioning of existing cardiomyocytes by, for example, inducing hypertrophy therein. Thus, the present compositions may serve the dual roles of stimulating fibroblast cells to engage in function(s) phenotypic of cardiomyocytes and stimulating hypertrophy in existing cardiomyocytes.

Problems solved by technology

Myocardial infarction results in the loss of cardiomyocytes.

The loss of cardiomyocytes leads to regional contractile dysfunction.

Although the transplantation of fetal cardiomyocytes is a proposed treatment of heart failure, it remains impractical in the clinical setting, in part because of the difficulty of obtaining fetal heart donor tissue.

Although it is known that the loss of post-mitotic cardiomyocytes results in increased morbidity and mortality, very little is known about the genes that are involved in heart development.

1997), Nkx2.5 / Csx, GATA4, and TEF-1 play important roles in cardiac development (Harvey, 1996), but the lack of a model for cardiomyocyte differentiation has hindered the understanding of the interactions of these genes.

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